KMI-1036 | 1022893-07-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: KMI-1036
• 英文别名: 2-(((2S,3S)-4-(3-(2H-tetrazol-5-yl)phenylamino)-3-hydroxy-4-oxo-1-phenylbutan-2-yl)carbamoyl)-6-((S)-4-phenyloxazolidine-3-carbonyl)pyridin-4-yl methanesulfonate；[2-[[(2S,3S)-3-hydroxy-4-oxo-1-phenyl-4-[3-(2H-tetrazol-5-yl)anilino]butan-2-yl]carbamoyl]-6-[(4S)-4-phenyl-1,3-oxazolidine-3-carbonyl]pyridin-4-yl] methanesulfonate
• CAS: 1022893-07-7
• 化学式: C₃₄H₃₂N₈O₈S
• 分子量: 712.743
• InChiKey: UVCVQGLBIJRFPT-DEIHTGSNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  51
• 可旋转键数：
  12
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  227
• 氢给体数：
  4
• 氢受体数：
  12

反应信息

• 作为产物：
  描述：

  4-methylsulfonyloxy-6-[(4S)-4-phenyl-1,3-oxazolidine-3-carbonyl]pyridine-2-carboxylic acid 、 (2S,3S)-3-amino-2-hydroxy-4-phenyl-N-[3-(2H-tetrazol-5-yl)phenyl]butanamide;hydrochloride 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 KMI-1036
  参考文献：
  名称：

  Novel non-peptidic and small-sized BACE1 inhibitors

  摘要：

  Recently, we reported substrate-based beta-secretase (BACE1) inhibitors with a hydroxymethylcarbonyl (HMC) isostere as a substrate transition-state mimic. These inhibitors showed potent BACE1 inhibitory activities (similar to 1.2 nM IC50). In order to improve in vivo enzymatic stability and permeability across the blood-brain barrier, these penta-peptidic inhibitors would need to be further optimized. On the other hand, non-peptidic inhibitors possessing isophthalic residue at the P-2 position were reported from other research groups. We selected isophthalic-type aromatic residues at the P-2 position and an HMC isostere at the P-1 position as lead compounds. On the basis of the design approach focused on the conformer of docked inhibitor in BACE1, we found novel non-peptidic and small-sized BACE1 inhibitors possessing a 2,6-pyridinedicarboxylic, chelidamic or chelidonic residue at the P2 position. (c) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2008.01.056

文献信息

• Novel non-peptidic and small-sized BACE1 inhibitors
  作者：Yoshio Hamada、Hiroko Ohta、Naoko Miyamoto、Ryoji Yamaguchi、Abdellah Yamani、Koushi Hidaka、Tooru Kimura、Kazuki Saito、Yoshio Hayashi、Shoichi Ishiura、Yoshiaki Kiso

  DOI：10.1016/j.bmcl.2008.01.056

  日期：2008.3

  Recently, we reported substrate-based beta-secretase (BACE1) inhibitors with a hydroxymethylcarbonyl (HMC) isostere as a substrate transition-state mimic. These inhibitors showed potent BACE1 inhibitory activities (similar to 1.2 nM IC50). In order to improve in vivo enzymatic stability and permeability across the blood-brain barrier, these penta-peptidic inhibitors would need to be further optimized. On the other hand, non-peptidic inhibitors possessing isophthalic residue at the P-2 position were reported from other research groups. We selected isophthalic-type aromatic residues at the P-2 position and an HMC isostere at the P-1 position as lead compounds. On the basis of the design approach focused on the conformer of docked inhibitor in BACE1, we found novel non-peptidic and small-sized BACE1 inhibitors possessing a 2,6-pyridinedicarboxylic, chelidamic or chelidonic residue at the P2 position. (c) 2008 Elsevier Ltd. All rights reserved.